There is a growing burden of bacterial infections worldwide and accurate diagnosis remains a cornerstone to providing accurate treatment.
Patients within hospitals and in healthcare generally, are at risk of bacterial infections. Hospital acquired infections (HAI) are becoming more common, and the ability to respond to such infections rapidly and accurately, is increasingly important. Where the patients have an active and healthy immune system, the dangers posed by HAI are reduced. However, the immune system of patients that are seriously ill are often at least partially compromised, making the patient especially vulnerable to HAIs.
Ventilated patients in critical care, and indeed all immunocompromised patients, are especially vulnerable to HAI, and one of the most devastating HAI remains ventilator associated pneumonia (VAP). VAP remains notoriously difficult to accurately diagnose and inappropriate treatment has been shown to be harmful to patients. Accordingly, VAP has a high mortality rate, significant morbidity and remains a burden on healthcare resources. In terms of diagnosis, the gold standard remains pulmonary biopsy, which is an invasive and rarely utilised investigation owing to the intrinsic invasive nature of the test. Other methods such as bronchoalveolar lavage remain controversial, while non-culture methods have not had any significant impact or robust validation. Clinical signs of fever, increased oxygen dependence and tachycardia remain as non-specific means of detecting inflammation or acute lung injury and therefore, alternative approaches are required that will allow the accurate and timely diagnosis of VAP, which will allow immediate healthcare decisions to be made and, with appropriate therapy, improve patient outcomes.
Currently clinicians are faced with significant uncertainty in relation to when and if to commence antibiotic treatment, the choice of agents to use, and if treatment begins, when to de-escalate therapy. These issues are barriers to effective antibiotic stewardship because of the proven association between delayed and inadequate antibiotic therapy and adverse clinical outcomes.
Molecular imaging technologies can allow the use of bacterial specific tracers and when combined with imaging modalities such as positron emission tomography (PET), have the ability to delineate infective from sterile sites. This approach, however is not be applicable for some patient groups, such as intensive care cohorts where a point of care diagnostic test would be required, and the administration of radioactive agents can be problematic and restrictive. These also involve radiation and are not readily applicable to imaging outside hospital settings.
An alternative approach in the art is the application of optical probes to allow direct visualisation of a target area of a patient, through the use of an endoscope. WO 2003/079015 in the name of Visen Medical, Inc., discloses optical imaging probes for identifying and characterising normal and diseased tissues with regards to altered metabolic activity.
WO 2012/136958 in the name of the present applicant discloses branched dyes to allow visualisation of cells in vivo by an increase in fluorescence when the dye is internalised by specific cell types.
However, there remains a need for improved optical probes and imaging methods that will allow in situ, point of care determination of whether a patient's condition is due to an infection, and if so, what is the causative agent of the infection.
Furthermore, there remains a need for improved optical probes that are retained at the target cell membrane, for example, during challenging conditions, such as in the presence of surfactants.
Therefore, an object of the present invention is to provide improved probes and imaging methods suitable for rapid and accurate point of care diagnosis, and to provide optical probes that are better retained by their target.